Commentary
Can Tissue-Based Immune Markers be Used for Studying the Natural History of Cancer?

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Introduction: Immunity and Cancer

Since the introduction of Burnet and Thomas’ cancer immunosurveillance hypothesis (1), the concept that the immune system plays a protective role in tumor development has been vigorously debated. The central principle of the hypothesis that the immune system can indeed prevent tumor formation was supported by clinical observations of higher incidences of cancer in immunodepressed individuals (2). Conversely, accumulated evidence showed that infectious and noninfectious causes of local chronic

Important Research Questions in Tumor Immunoepidemiology

Many epidemiologic studies only collect tissue specimens at a single time point, typically the time of diagnosis or selection into the study, which potentially limits the research questions that can be addressed. One of the most explored research questions in individuals with disease has been this: What is the association between the presence of certain immune infiltrates and clinical outcomes such as prognosis and survival? Such analyses have been reported in several solid cancers, including

Why Tissue-Based Markers?

Broadly defined, tissue-based immune markers may refer to markers of specific immune cell populations, the expression of specific cytokines in tissues by immune cells that play a role in immune function or signaling, cytokine receptors, or immune presentation molecules (human leukocyte antigen). Tissue-based markers are likely to become more and more available given the increasing use of biomarkers in clinical care and advances in biomarker discovery and technological innovation (14).

Examples of Tissue-Based Immune Markers

Immune cells and the cellular factors produced from them, both immunosuppressive and inflammatory cytokines, play dual roles in promoting or discouraging cancer development. Their role may be determined by the tumor microenvironment and the events that lead to the initial propagation of carcinogenesis. Of the plethora of cells, cytokines, or other soluble factors involved, tumor-associated macrophages or myeloid-derived suppressive cells and secreted cytokines interleukin (IL)-6, tumor necrosis

Tools for Studying Tissue-Based Immune Markers

Immunity and inflammation at the cancer site can be evaluated using various molecular techniques, depending on the type of tissue that is available and the assessments desired (Table 1 lists some examples described here). The type, density, and location of immune cells can be assessed in fresh and ethanol- or formalin-fixed tumor tissues. Previous studies [e.g., 7, 8, 28, 29, 30, 31, 32, 33] have semiquantitatively evaluated the numbers and proportion of various immune cell subsets, including

Study Populations and Study Design

One of the first considerations of study design is the choice of the most appropriate population for evaluating the question of interest. Importantly, studies in the general population allow for conclusions regarding interventions that may affect public health, such as cancer screening. However, in-depth studies of biological mechanisms might require studies in special populations at high risk for certain outcomes of interest (e.g., referral clinic patients).

Several study designs can be applied

Efficiency for Studying Tissue-Base Immune Markers: Prospective Versus Cross-Sectional Design

Prospective data from cohorts or trials are often preferable because temporality may potentially be evaluated. For tissue-based studies, however, cross-sectional designs in high-risk populations may be more feasible and efficient. A comparison of two National Cancer Institute studies of cervical cancer, the Guanacaste Project and the Study to Understand Cervical Cancer Early Endpoints and Determinants (SUCCEED), provides an excellent example. The Guanacaste Project is a cohort study that began

Sample Size Considerations

Four quantities are needed to calculate sample sizes: (1) the expected difference (e.g., mean difference) or association (e.g., odds ratio), (2) an estimate of the variability in the measurements (e.g., standard deviation, standard error, or 95% confidence interval), (3) the desired statistical power (e.g., 0.8 or 0.9), and (4) the number of comparisons and whether the comparisons are agnostic (i.e., no a priori hypotheses, and typically numerous) or based on biologically plausible, a priori

Potential Confounders

Studies of immune response must also consider potential confounders. For example, age may be associated with both immunity and cancer. In our previous example of immune markers in precursor lesions, precursors typically occur in individuals at a younger age than cancer, and immunity declines with age (63). Thus, age should be accounted for carefully. Immunity also differs for men and women (64), so it is important to consider gender for non–gender-specific cancers. Race/ethnicity has been

Tissue-Based Immune Markers and the Natural History of Cancer

An important goal is to establish how immune response contributes to the development of cancer. Immune markers that are present at the time of cancer diagnosis may reflect the immune function that contributed to the development of cancer or may be the result of the cancer itself. Therefore, disease effects may be best addressed in subjects with precursor conditions. Comparisons of tissue-based immune markers from low-grade precursor conditions to cancer, as well as the range of stages among

An Integrative Approach

Although tissue-based measures are not without limitations, they contribute to our understanding of the role of immune factors in the development of cancer, especially by combining them with other studies of immune markers that have different strengths and limitations. In particular, genetic studies of polymorphisms in immune pathways provide information on the association between inherited differences in immune-related pathways and cancer risk. For example, polymorphisms in the IL1β and the

Conclusions

Tissue-based studies can be used to examine associations between immune markers and cancer outcomes, evaluate and possibly discover new tumor subtypes, and identify clues to the biological mechanisms that contribute to the development of cancer. For each of these approaches, it is important to consider the characteristics of the study population, choose the most suitable study design, use proper techniques to select study participants and their biological samples, employ validated, reliable

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